Cancer is a leading cause of death worldwide, and mortality is largely attributed to cancers of epithelial origin, i.e., carcinomas of the lung, colon, breast, liver, stomach, prostate, ovary, endometrium and pancreas (Parkin et al., 2001). Survival rates are dramatically improved when carcinomas are diagnosed early and the disease is limited to the organ of origin. Indeed, physical methods for screening like pap smears in cervical cancer and mammography in breast cancer have dramatically reduced mortality rates (Marcial, 1977, Nelson et al., 2009b). Thus, research towards developing new early detection biomarkers in easily accessible body fluids, such as serum, urine or saliva has been encouraged (Srivastava and Gopal-Srivastava, 2002). Some well-known biomarkers (Nossov et al., 2008, Candefjord et al., 2009, Greene et al., 2009, Gupta and L is, 2009, Nelson et al., 2009a, Nogueira et al., 2009, van Leeuwen et al., 2009) are reliably detected in advanced stages of disease, but lack sufficient sensitivity and especially specificity for early cancer diagnosis, and are thus used mainly for prognosis, staging, monitoring and selection of therapy (Ludwig and Weinstein, 2005).
An alternative promising strategy is to take advantage of the immune response to cancer, which can be elicited at an early stage during tumorigenesis. This is partially manifested by production of autoantibodies against tumor-associated antigens (Raedle et al., 1998, Soussi, 2000, Desmetz et al., 2009a, Desmetz et al., 2009b, Tan et al., 2009). However, specificity and sensitivity have been limited mainly owing to the heterogenous nature of cancer, where different proteins are aberrantly processed or regulated in patients with the same type of cancer, causing much variability in the immune response (Raedle et al., 1998, Soussi, 2000, Tan et al., 2009).
Novel serum biomarkers for cancer screening are needed, since current ones lack sufficient sensitivity and especially specificity for early diagnosis (18, 19), being reliably detected mainly in advanced stages, and thus used more for prognosis, staging, monitoring and therapy selection (18). While antibodies against tumor-associated antigens are commonly found in cancer patients at an early stage and could potentially be sensitive detectors for malignant transformation (21, 22), none of the previously described autoantibodies show sufficient specificity in screening.
Available blood based assays have minimal clinical utility for the early diagnosis of cancer due to poor sensitivity and specificity. Generally they are used for monitoring the treatment of metastatic cancer. Prostate specific antigen (PSA), which is widely used to screen for prostate cancer, is the best example of a useful blood based cancer screening assay and in recently published randomized studies has marginal clinical utility. The following blood based cancer tests are used; PSA, CA27.29, CA19.9, CA125, CEA, and αFP. Aside from PSA only αFP is used as a screening test, in this case for patients with hepatitis C induced cirrhosis at high risk for hepatocellular carcinoma. None of these tests has been shown to reduce cancer specific mortality with a reasonable financial or morbidity cost. Nevertheless, PSA and αFP screening as well as CA125 screening are often used due to the profound need for blood based cancer screening.
Despite advances in the art, there remains a need for improved biomarkers for cancer screening.